Hepatitis C (HCV) is the most comon blood-born infection in the United States, where about 35,000 new cases are estimeted to occur each year. There is currently a need for compounds, compositions, and methods that are useful for treating viral infections such as HCV. This project involved novel compounds that inhibit one or more viral proteases. Accordingly, the compounds may be useful for treating viruses, such as HCV. We have explored the structure activity of nucleoside analogues synthesized in our laboratory in models of HCV, including NS5b polymerase assay and the replicon assay. Ring constrained analogues of purine and pyrimidine nucleotides have been explored as inhibitors.